title: Integrative analysis of deep sequencing data identifies estrogen receptor early response genes and links ATAD3B to poor survival in breast cancer.
abstract: Identification of responsive genes to an extra-cellular cue enables characterization of pathophysiologically crucial biological processes. Deep sequencing technologies provide a powerful means to identify responsive genes, which creates a need for computational methods able to analyze dynamic and multi-level deep sequencing data. To answer this need we introduce here a data-driven algorithm, SPINLONG, which is designed to search for genes that match the user-defined hypotheses or models. SPINLONG is applicable to various experimental setups measuring several molecular markers in parallel. To demonstrate the SPINLONG approach, we analyzed ChIP-seq data reporting PolII, estrogen receptor α (ERα), H3K4me3 and H2A.Z occupancy at five time points in the MCF-7 breast cancer cell line after estradiol stimulus. We obtained 777 ERa early responsive genes and compared the biological functions of the genes having ERα binding within 20 kb of the transcription start site (TSS) to genes without such binding site. Our results show that the non-genomic action of ERα via the MAPK pathway, instead of direct ERa binding, may be responsible for early cell responses to ERα activation. Our results also indicate that the ERα responsive genes triggered by the genomic pathway are transcribed faster than those without ERα binding sites. The survival analysis of the 777 ERα responsive genes with 150 primary breast cancer tumors and in two independent validation cohorts indicated the ATAD3B gene, which does not have ERα binding site within 20 kb of its TSS, to be significantly associated with poor patient survival.
authors.affiliation: Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: Kristian
authors.initials: K
authors.lastname: Ovaska
authors.forename: Filomena
authors.initials: F
authors.lastname: Matarese
authors.forename: Korbinian
authors.initials: K
authors.lastname: Grote
authors.forename: Iryna
authors.initials: I
authors.lastname: Charapitsa
authors.forename: Alejandra
authors.initials: A
authors.lastname: Cervera
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: George
authors.initials: G
authors.lastname: Reid
authors.forename: Martin
authors.initials: M
authors.lastname: Seifert
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D016019:Survival Analysis; D014158:Transcription, Genetic
chemical_list: C519737:ATAD3B protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities